Imperial College London

Henry Rzepa

One future vision for chemistry over the next 20 years or so is the
concept of having machines into which one *dials a molecule*, and as if
by magic, the required specimen is ejected some time later. This is in
some ways an extrapolation of the existing peptide and nucleotide
synthesizer technologies and sciences. A pretty significant
extrapolation, suitable no doubt for a grand future challenge in
chemistry (although the concept of tumbling a defined collection of
atoms in a computer model and seeing what interesting molecules emerge,
dubbed with some sense of humour as m*indless chemistry*, is already
being done; see DOI:
[10.1021/jp057107z](http://dx.doi.org/10.1021/jp057107z){target="_blank"}).

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[![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/03/sultine.jpg "sultine"){.size-full
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A possible carbene transfer reagent
:::

Well, let us return to present day reality (I know it was a little
unfair to capture your attention with such a grand title!). Consider the
sequence above. Sulfenes are known simple elaborations of sulfur
trioxide, with one oxygen replaced by a CH~2~ group. They can exist as
isomeric rings, known as sultines (and which are of similar energy to
the sulfenes, see DOI:
[10.1016/j.theochem.2007.10.035](http://dx.doi.org/10.1016/j.theochem.2007.10.035){target="_blank"}).
Few people have speculated upon what might be done with this small
collection of atoms. It struck me (I am unaware it has struck anyone
else, but I am happy to be corrected) that it might be useful as a
reagent for delivering a carbene. The precedent is that oxaziridines (in
which the SO unit is replaced by *e.g.* NR) can be used to transfer
either oxygen or NR to alkenes, and dioxiranes (in which the SO unit is
replaced by an oxygen) are very useful reagents for oxygen transfer to
an alkene. In the example of the sultine, loss instead of carbene
(CH~2~) would result in the thermodynamically stable sulfur dioxide.
Also apparent is that the sultine is asymmetric (chiral) and so perhaps
there is also a prospect of delivering that carbene asymmetrically (a
reaction normally done with the help of metal catalysts). As shown
above, the carbene is also nucleophilic, rather than electrophilic,
which may also be useful in some contexts.

Enter the computer, which will be used to see if these simple ideas can
be turned into the design of a new reaction. Firstly, the assertion that
the reaction producing cyclopropane and sulfur dioxide is exothermic is
easily tested (B3LYP/cc-pVTZ); it comes out as exothermic in free energy
by -26.6 kcal/mol (some of which of course is due to entropy). Next, the
transition state for the delivery.

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width="292" height="176"}

Transition state for carbene transfer from sulfine
:::

This emerges (DOI: [10042/to-4476](http://hdl.handle.net/10042/to-4476))
with a free energy barrier of 37.4 kcal/mol relative to the sultine.
Rather too high a barrier to constitute a useful synthetic reaction! But
there is something interesting to be learnt from this transition state.
Whilst the product is clearly cyclopropane and sulfur dioxide, the
reactant is not the sultine but appears to be another species, labelled
above as the *1,3 dipole* (DOI:
[10042/to-4487](http://hdl.handle.net/10042/to-4487)), a species which
is 13 kcal/mol higher in free energy than the sultine itself (but does
it have to be formed first, or is it merely on the reaction path?).
There are other noteworthy aspects of the transition state. The carbene
cycloaddition is a 4n electron process, with an apparent *antarafacial*
component, this mapping onto inversion at the carbene centre. The bond
formation at the alkene is very *asynchronous*, and the SO~2~ unit
clearly does appear to act as a chiral auxilliary. Also these aspects
would have to be factored into the eventual design.

We now enter an optimization stage of the process, in which we try to
reduce the activation barrier in order to produce a viable reaction.
Replacing CH~2~ by CF~2~ however increases the barrier to 42.5 kcal/mol,
whilst substituting Se for S induces a barrier of 40.6 kcal/mol. More
variation of the various substituents (including the alkene) will be
needed to see if such a reaction could actually be carried out, but this
is relatively routine process, not attempted here (perhaps not entirely
routine; thus predicting what might happen is easy compared to analyzing
what **does not happen**, see DOI:
[10.1002/anie.200801206](http://dx.doi.org/10.1002/anie.200801206){target="_blank"}). So,
there is certainly no claim here that a new reaction has been designed.
Rather a tentative hint at the kind of processes that might be involved,
eventually, in *dialing a molecule*.

::: {.wp_orcid_field}
[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
:::


One future vision for chemistry over the next 20 years or so is the concept of having machines into which one
<em>
 dials a molecule
</em>
, and as if by magic, the required specimen is ejected some time later. This is in some ways an extrapolation of the existing peptide and nucleotide synthesizer technologies and sciences.

Publicaciones de Rogue Scholar

Dial a molecule: Can new reactions be designed by computer?